Hormonal and Nutritional Control of the Fatty Acid Synthase Promoter in Transgenic Mice

Soncini, Chiara; Yet, Shaw‐Fang; Moon, Yangha Kim; Chun, Jong-Yoon; Sul, Hei Sook

doi:10.1074/jbc.270.51.30339

Cited by 67 publications

(49 citation statements)

References 29 publications

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“…In contrast, transgenic mice carrying CAT driven by longer 5Ј-flanking sequence (Ϫ644-FAS-CAT and Ϫ444-FAS-CAT) showed a CAT mRNA expression pattern identical to that of Ϫ2100-FAS-CAT transgenic mice and produced high levels of CAT expression in liver and white and brown adipose tissue only. The tissue distribution of the CAT mRNA in transgenic mice carrying Ϫ2100-FAS-CAT, Ϫ644-FAS-CAT, and Ϫ444-FAS-CAT fusion genes paralleled that of the endogenous FAS mRNA, which is highly expressed only in lipogenic tissues (liver and adipose tissue) (18), when determined using the same RNA preparations. Actin mRNA (used as a control) was uniformly expressed in all of the tissues we studied.…”

Section: Expression Of the Fas Promoter-cat Fusion Gene In Trans-mentioning

confidence: 93%

“…However, all of the cis-acting sequences identified to date were defined using in vitro culture systems, and the significance of these regulatory elements to in vivo events needs to be established. The only report that addresses the sequence requirement for the FAS gene in vivo is our previous 2.1-kb FAS promoter-CAT transgenic mice studies (18). By examining the transgene expression under various hormonal/ nutritional conditions, we demonstrated that the 2.1-kb 5Ј-flanking sequence is sufficient for tissue-specific and hormonal/ nutritional regulation of the FAS gene in the in vivo context.…”

mentioning

confidence: 94%

“…Plasmid Construction and Production of Transgenic Mice-The Ϫ2100-FAS-CAT plasmid containing Ϫ2100 to ϩ67 bp of the rat FAS gene in pBLCAT3 has been described previously (18). Transgenic mice harboring Ϫ644-FAS-CAT were generated by injection of an agarose gel-purified NarI-KpnI fragment from the Ϫ2100-FAS-CAT plasmid containing from Ϫ644 to ϩ67 bp of the FAS promoter, CAT, and SV40 polyadenylation sequences into pronuclei of fertilized mouse embryos (Brigham Women's Hospital Transgenic Mice Facility of the Harvard Medical School).…”

Section: Methodsmentioning

confidence: 99%

“…genic Mice-We previously reported that 2.1 kb of the 5Ј-flanking sequence are sufficient for tissue-specific and hormonally regulated expression of the FAS gene in vivo (18). To examine the DNA regions responsible for tissue-specific and hormonal/ nutritional regulation of the rat FAS gene in vivo, we have generated multiple lines of transgenic mice carrying the CAT reporter gene driven by various 5Ј-deletions of the FAS 5Ј-flanking sequence.…”

Section: Expression Of the Fas Promoter-cat Fusion Gene In Trans-mentioning

confidence: 99%

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Two 5′-Regions Are Required for Nutritional and Insulin Regulation of the Fatty-acid Synthase Promoter in Transgenic Mice

Moon

Latasa

Kim

et al. 2000

Journal of Biological Chemistry

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We previously reported that 2.1 kilobase pairs of the 5-flanking sequence are sufficient for tissue-specific and hormonal/metabolic regulation of the fatty-acid synthase (FAS) gene in transgenic mice. We also demonstrated that the ؊65 E-box is required for insulin regulation of the FAS promoter using 3T3-L1 adipocytes in culture. To further define sequences required for FAS gene expression, we generated transgenic mice carrying from ؊644, ؊444, ؊278, and ؊131 to ؉67 base pairs of the rat FAS 5-flanking sequence fused to the chloramphenicol acetyltransferase (CAT) reporter gene. Similar to the expression observed with ؊2100-FAS-CAT transgenic mice, transgenic mice harboring ؊644-FAS-CAT and ؊444-FAS-CAT expressed high levels of CAT mRNA only in lipogenic tissues (liver and adipose tissue) in a manner identical to the endogenous FAS mRNA. In contrast, ؊278-FAS-CAT and ؊131-FAS-CAT transgenic mice did not show appreciable CAT expression in any of the tissues examined. When previously fasted mice were refed a high carbohydrate, fat-free diet, CAT mRNA expression in transgenic mice harboring ؊644-FAS-CAT and ؊444-FAS-CAT was induced dramatically in liver and adipose tissue. The induction was virtually identical to that observed in ؊2100-FAS-CAT transgenic mice and to the endogenous FAS mRNA. In contrast, ؊278-FAS-CAT transgenic mice showed induction by feeding, but at a much lower magnitude in both liver and adipose tissue. The ؊131-FAS-CAT transgenic mice did not show any CAT expression either when fasted or refed a high carbohydrate diet. To study further the effect of insulin, we made these transgenic mice insulin-deficient by streptozotocin treatment. Insulin administration to the streptozotocin-diabetic mice increased CAT mRNA levels driven by the ؊644 FAS and ؊444 FAS promoters in liver and adipose tissue, paralleling the endogenous FAS mRNA levels. In the case of ؊278-FAS-CAT, the induction observed was at a much lower magnitude, and deletion to ؊131 base pairs did not show any increase in CAT expression by insulin. This study demonstrates that the sequence requirement for FAS gene regulation employing an in vitro culture system does not reflect the in vivo situation and that two 5-flanking regions are required for proper nutritional and insulin regulation of the FAS gene. Cotransfection of the upstream stimulatory factor and various FAS promoter-luciferase constructs as well as in vitro binding studies suggest a function for the upstream stimulatory factor at both the ؊65 and ؊332 E-box sequences. Fatty-acid synthase (FAS)1 plays a central role in de novo lipogenesis in mammals (1). By the action of its seven active sites, FAS catalyzes all the reaction steps in the conversion of acetyl-CoA and malonyl-CoA to palmitate. FAS activity is not known to be regulated by allosteric effectors or covalent modification. However, the FAS concentration is exquisitely sensitive to nutritional, hormonal, and developmental status in lipogenic tissues (liver and adipose tissue) (1, 2). The concentration or enzyme activity of...

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Section: Expression Of the Fas Promoter-cat Fusion Gene In Trans-mentioning

confidence: 93%

mentioning

confidence: 94%

Section: Methodsmentioning

confidence: 99%

Section: Expression Of the Fas Promoter-cat Fusion Gene In Trans-mentioning

confidence: 99%

See 2 more Smart Citations

Two 5′-Regions Are Required for Nutritional and Insulin Regulation of the Fatty-acid Synthase Promoter in Transgenic Mice

Moon

Latasa

Kim

et al. 2000

Journal of Biological Chemistry

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“…In our NRVM cultures, we have detected significant mRNA expression and induction by FN of fatty acid synthetase (Fasn) and other genes in the fatty acid biosynthesis pathway. Other studies have detected Fasn mRNA in the heart and reported regulation by starvation (28), glucocorticoids (48), and thyroid hormone (4). It is possible that in the perfused adult heart (16, 21) fatty acid synthesis is undetectable, but in cultured NRVM fatty acid synthesis plays a role in hypertrophic growth.…”

Section: Fibronectin-induced Cardiomyocyte Hypertrophymentioning

confidence: 99%

Gene expression changes associated with fibronectin-induced cardiac myocyte hypertrophy

Chen

Huang

Stewart

et al. 2004

Physiological Genomics

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(FN) is an extracellular matrix protein that binds to integrin receptors and couples cardiac myocytes to the basal lamina. Cardiac FN expression is elevated in models of pressure overload, and FN causes cultured cardiac myocytes to hypertrophy by a mechanism that has not been characterized in detail. In this study, we analyzed the gene expression changes induced by FN in purified rat neonatal ventricular myocytes using the Affymetrix RAE230A microarray, to understand how FN affects gene expression in cardiac myocytes and to separate the effects contributed by cardiac nonmyocytes in vivo. Pathway analysis using z-score statistics and comparison with a mouse model of cardiac hypertrophy revealed several pathways stimulated by FN in cardiac myocytes. In addition to the known cardiac myocyte hypertrophy markers, FN significantly induced metabolic pathways including virtually all of the enzymes of cholesterol biosynthesis, fatty acid biosynthesis, and the mitochondrial electron transport chain. FN also increased the expression of genes coding for ribosomal proteins, translation factors, and the ubiquitin-proteasome pathway. Interestingly, cardiac myocytes plated on FN showed elevated expression of the fibrosis-promoting peptides connective tissue growth factor (CTGF), WNT1 inducible signaling pathway protein 2 (WISP2), and secreted acidic cysteine-rich glycoprotein (SPARC). Our data complement in vivo studies and reveal several novel genes and pathways stimulated by FN, pointing to cardiac myocyte-specific mechanisms that lead to development of the hypertrophic phenotype. extracellular matrix; integrin; ventricular remodeling; signal transduction; gene expression profiling OUTSIDE-IN SIGNALING CHARACTERIZES the cellular effects mediated by interaction of cellular receptors with the extracellular matrix. In neonatal rat ventricular myocytes (NRVM), clustering of integrin receptors induced by fibronectin (FN) (39,40) or RGD peptides (3) elicits a hypertrophic response, characterized by a 1.5-to 3-fold increase in cellular area and corresponding increases in global mRNA and protein synthesis, together with enhanced myofibrillogenesis and sarcomeric assembly. FN also induces increased formation of focal adhesions and costameres, which are sites of contact of extracellular matrix with integrins and associated cytoskeletal proteins associated with the Z-disks of the sarcomere (39). As in other models of hypertrophy, the hypertrophic response is accompanied by changes in gene expression, with increased expression of the natriuretic peptides atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) and fetal isoforms of sarcomeric proteins such as ␤-myosin heavy chain (␤MHC) and ␣-skeletal actin (␣SkA).The pathophysiological relevance of the FN-induced, integrin-mediated pathway is highlighted by the observation of increased deposition of FN in the extracellular matrix in animal models of cardiac hypertrophy and in patients with cardiac failure (5,20,22,29,42,45). The increased synthesis of FN is in part mediated...

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Regulation of Fatty Acid Biosynthesis and Lipolysis

Salati

2001

Comprehensive Physiology

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The sections in this article are: Pathways of De Novo Fatty Acid Biosynthesis and Lipolysis Regulation in the Pathways for Lipogenesis and Lipolysis Cellular Sites of Lipogenesis and Lipolysis Isolated Cell Models for the Study of Lipogenesis and Lipolysis Establishing Insulin and Glucagon as Regulators of Lipogenesis and Lipolysis Molecular Mechanisms Involved in the Regulation of Lipogenesis and Lipolysis Criteria for Evaluating Putative Regulatory Mechanisms Regulated Steps Summary

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Hormonal and Nutritional Control of the Fatty Acid Synthase Promoter in Transgenic Mice

Cited by 67 publications

References 29 publications

Two 5′-Regions Are Required for Nutritional and Insulin Regulation of the Fatty-acid Synthase Promoter in Transgenic Mice

Two 5′-Regions Are Required for Nutritional and Insulin Regulation of the Fatty-acid Synthase Promoter in Transgenic Mice

Gene expression changes associated with fibronectin-induced cardiac myocyte hypertrophy

Regulation of Fatty Acid Biosynthesis and Lipolysis

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